In this project, we will investigate the transcriptomes of a human brain tissue to resolve RNA transcripts and functional variants that contribute to the process of cognitive decline in the aging human brain. Our approach using next generation RNA sequencing to create these transcriptomes will allow an unparalleled perspective on the complexity of transcriptional regulation of the brain, which is a tissue with one of the most diverse content of alternatively spliced transcripts and non-coding RNA molecules, many of which may not have been previously discovered. Further, the availability of genome-wide genotype data on the same subjects gives us a unique opportunity to explore the genetic effects on RNA expression. Thus, we may gain insight not only into the transcriptome diversity of the aging human brain but also into the manner in which genetic variation associated with clinically impaired cognition exert a functional consequence on the human brain. ! ! PUBLIC HEALTH RELEVANCE: The goal of this proposal is to understand which molecules of a brain tissue are involved in the cognitive decline in older individuals. In understanding how these molecules relate to genetic risk for aging and human cognitive function will allow investigators to better understand the onset of cognitive decline and diseases of cognition, such as Alzheimer's disease (AD). This may help to develop clinical tests that may be able to predict who is at risk of developing AD and to develop new treatments to delay or prevent onset of cognitive decline and AD.